To the Editor: We are concerned that a recent report announced that the Queensland Ambulance Service now treats patients with hypertension caused by Irukandji syndrome with sublingual glyceryl trinitrate, based on an uncontrolled, unrandomised, unblinded “trial” of three patients.1 We believe the authors have made the justification for such treatment on questionable assumptions.

The authors claim that venom from Carukia barnesi is a sodium channel agonist that causes massive noradrenaline release. This claim is based on a letter which reported whole C. barnesi being crudely blended and injected into piglets.2 There is no mention in this letter of any proven sodium channel agonist action.2 We are unconvinced that it was solely the venom of the jellyfish that resulted in a rise in noradrenaline levels in the piglets, especially since there has been a recent report of toxicity from homogenised jellyfish with the nematocysts (ie, venom) removed.3

While we believe that magnesium may be a promising treatment for patients with Irukandji syndrome, there has only been one case reported,4 and we are aware of several anecdotal failures, including the first patient in the letter by Fenner and Lewin.1 This does not constitute the justification for “proven effective treatment”.

Fenner and Lewin claim that patients were envenomed by Carukia barnesi and yet provide no evidence. Carukia barnesi has yet to be discovered or reported south of Townsville. Two of us have reported that more than one jellyfish is responsible for Irukandji syndrome, and a second jellyfish has recently been identified.5 Accurate identification of the envenoming animal is essential in toxinology.

Patients who present with Irukandji syndrome are in severe pain, and pain is a well known cause of hypertension. In a series of 116 patients with Irukandji syndrome, the mean dose of morphine administered was 31 mg.6 In the three patients reported by Fenner and Lewin, all were in severe pain, but only received 10 mg of morphine. In light of subtherapeutic analgesia, attributing the persistent hypertension solely to an unmanageable disease process is therefore premature and possibly incorrect. As a further confounder, might the reduction of blood pressure in two patients have resulted from the delayed onset of action of intramuscular morphine and promethazine? Without the addition of control patients to this trial, no conclusions can be drawn on the causative factors associated with this treatment.

Too often in the past, unsupported treatments have been adopted, only to be abandoned several years later when shown to be ineffectual, or even dangerous to patients. There are too many assumptions, unsupported claims and confounders in Fenner and Lewin’s letter. Toxinology research needs good science and not poor anecdotes.

To the Editor: Fenner and Lewin describe three cases of Irukandji syndrome in which glyceryl trinitrate (GTN) was used to transiently lower blood pressure.1 However, they provide no evidence that this relieved the patients’ pain or improved their ultimate outcome (development of pulmonary oedema or myocardial injury); they therefore do not show sufficient evidence for instituting such therapy. It is worrying that, with little evidence, sublingual GTN is now recommended as a prehospital treatment in Irukandji syndrome. Although GTN has been used safely in other conditions, its use without adverse effects in three patients is not evidence that it can be used safely in treating jellyfish envenoming.

It is of concern that the treatment of bites and stings remains based on anecdotal evidence, and that clinical toxinology has not moved with the rest of medicine to developing evidence-based approaches. Fenner and Lewin state, in their second paragraph, that intravenous magnesium has proven to be effective in treating symptoms of Irukandji syndrome. This is based on a single case report and no controlled trials. It simply provides a starting point so that properly designed studies can be done to determine if magnesium is effective and safe in Irukandji syndrome. It is not appropriate to suggest that magnesium is a proven therapy without further investigation.

Are we not learning from previous problems in clinical toxinology and prehospital care? Both are areas of medicine where treatment protocols are rarely based on substantial evidence.2,3 The pressure immobilisation bandage was introduced for the first-aid treatment of Chironex fleckeri stings with no supporting evidence, and it has taken two well designed animal studies to show that this is dangerous.4,5 A recent well designed study in the United States showed that prehospital intubation by paramedics of patients with head injury resulted in transient desaturation in 57% of patients and significant bradycardia (< 50 bpm) in 19%.6 This occurred despite the paramedics describing the intubation as “easy” in 84% of the patients who desaturated. This shows that it is essential to properly evaluate the safety and efficacy of treatments before recommending them for prehospital use.

Although the infrequency of many envenoming syndromes makes controlled studies difficult to do, it is essential that clinical investigators collaborate to institute such studies. This is now happening in Australia with the commencement of randomised controlled trials on redback spider antivenom, magnesium in Irukandji syndrome and hot-water first-aid in jellyfish stings. Hopefully we will move from anecdote to evidence in clinical toxinology with collaborative studies such as these.

In reply: We did not provide evidence of any effect on pulmonary oedema, myocardial injury or any effect in stopping pain, as that was not our intention. Also, even intravenous nitrates that have been used for many years in hospital are ineffective in reducing the muscle-cramping pains of Irukandji envenomation, and, although they reduce hypertension and ischaemic myocardial pain, there is no correlation or evidence that they prevent pulmonary oedema or myocardial injury.

The assumption that the Queensland Ambulance Service (QAS) introduced this treatment after our trial is incorrect. The QAS Medical Director will confirm that it was introduced independently of our trial and actually before we treated our first case.

While pain causes hypertension, in our Patient 1 effective analgesia had been attained without any effect on his hypertension. Also, many patients with Irukandji syndrome have pain without hypertension, while others have severe hypertension even with effective pain control.1 Further evidence that the venom from Carukia barnesi is a sodium channel modulator has been submitted for publication (Ken Winkel, Director, Australian Venom Research Unit, Melbourne, personal communication).

Carukia barnesi has now been caught in the Mackay region, 400 kilometres south of Townsville (identified by me, and confirmed by L A Gershwin, PhD student in cubozoan taxonomy, James Cook University, 2003, personal communication). A number of other species can cause the Irukandji syndrome, but the jellyfish causing the sting is rarely caught, so cause and effect are hard to establish at present.

Our aim was to present early evidence that sublingual nitrates may be effective in reducing the hypertension that occurs in some cases of Irukandji syndrome; our suggestion was that they be further trialled.2 It seems worthwhile to do so, especially as sublingual nitrates have also been shown to be effective in dysreflexia from spinal injury,3 where hypertension also occurs from the massive release of similar catecholamines.

At least two deaths have occurred after Irukandji envenomation, both as a result of cerebrovascular accidents from severe hypertension.4 When treating a patient with severe hypertension from Irukandji envenomation in a prehospital situation, it is reasonable to try to reduce the hypertension. Doing so might reduce the risk of a cerebrovascular accident and possible death, and so further trials of this prehospital treatment must take place. Other prehospital treatments must also be trialled, especially those for pain. Early promising leads need to be published early for all to evaluate. The Irukandji syndrome is a dreadful experience for the victim; all possible prehospital relief measures must be tried and evaluated.

Comment: I would like to clarify a few points. Firstly, all Queensland Ambulance Service (QAS) paramedics use glyceryl trinitrate (GTN) frequently to treat cardiac chest pain, and have done so for many years. They are very familiar with its effects and interactions.

Secondly, a small number of intensive care paramedics (ICPs), the top tier of officer, with many years of training and experience and tertiary qualifications, have, for a number of years, been authorised to consult with the senior doctor at the receiving hospital for use of GTN to treat acute severe hypertension. In Queensland, GTN has been used for this indication in one or two patients per year, compared with its use in 25 000 patients with cardiac chest pain.

Finally, QAS reviewed its protocol for managing marine envenomation after two people died from Irukandji syndrome two years ago. The current protocol for suspected Irukandji stings is now standard care, including oxygen, and vinegar if there is a visible sting, followed by aggressive pain management, including up to 30 mg of morphine intravenously. If the patient has significant hypertension (> 200/120 mmHg) after effective analgesia, ICP officers are able to consult with a senior doctor to administer GTN according to the above protocol. Obviously, the concern of the QAS Medical Advisory Council (comprising representatives of all medical specialty colleges and other medical groups) was to prevent avoidable cerebral haemorrhage or acute heart failure, as occurred in the two deaths from Irukandji syndrome, but, to date, such use of GTN has not been invoked.